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BACKGROUND: The extended acquisition times required for MRI limit its availability in resource-constrained settings. Consequently, accelerating MRI by undersampling k-space data, which is necessary to reconstruct an image, has been a long-standing but important challenge. We aimed to develop a deep convolutional neural network (dCNN) optimisation method for MRI reconstruction and to reduce scan times and evaluate its effect on image quality and accuracy of oncological imaging biomarkers. METHODS: In this multicentre, retrospective, cohort study, MRI data from patients with glioblastoma treated at Heidelberg University Hospital (775 patients and 775 examinations) and from the phase 2 CORE trial (260 patients, 1083 examinations, and 58 institutions) and the phase 3 CENTRIC trial (505 patients, 3147 examinations, and 139 institutions) were used to develop, train, and test dCNN for reconstructing MRI from highly undersampled single-coil k-space data with various acceleration rates (R=2, 4, 6, 8, 10, and 15). Independent testing was performed with MRIs from the phase 2/3 EORTC-26101 trial (528 patients with glioblastoma, 1974 examinations, and 32 institutions). The similarity between undersampled dCNN-reconstructed and original MRIs was quantified with various image quality metrics, including structural similarity index measure (SSIM) and the accuracy of undersampled dCNN-reconstructed MRI on downstream radiological assessment of imaging biomarkers in oncology (automated artificial intelligence-based quantification of tumour burden and treatment response) was performed in the EORTC-26101 test dataset. The public NYU Langone Health fastMRI brain test dataset (558 patients and 558 examinations) was used to validate the generalisability and robustness of the dCNN for reconstructing MRIs from available multi-coil (parallel imaging) k-space data. FINDINGS: In the EORTC-26101 test dataset, the median SSIM of undersampled dCNN-reconstructed MRI ranged from 0·88 to 0·99 across different acceleration rates, with 0·92 (95% CI 0·92-0·93) for 10-times acceleration (R=10). The 10-times undersampled dCNN-reconstructed MRI yielded excellent agreement with original MRI when assessing volumes of contrast-enhancing tumour (median DICE for spatial agreement of 0·89 [95% CI 0·88 to 0·89]; median volume difference of 0·01 cm3 [95% CI 0·00 to 0·03] equalling 0·21%; p=0·0036 for equivalence) or non-enhancing tumour or oedema (median DICE of 0·94 [95% CI 0·94 to 0·95]; median volume difference of -0·79 cm3 [95% CI -0·87 to -0·72] equalling -1·77%; p=0·023 for equivalence) in the EORTC-26101 test dataset. Automated volumetric tumour response assessment in the EORTC-26101 test dataset yielded an identical median time to progression of 4·27 months (95% CI 4·14 to 4·57) when using 10-times-undersampled dCNN-reconstructed or original MRI (log-rank p=0·80) and agreement in the time to progression in 374 (95·2%) of 393 patients with data. The dCNN generalised well to the fastMRI brain dataset, with significant improvements in the median SSIM when using multi-coil compared with single-coil k-space data (p<0·0001). INTERPRETATION: Deep-learning-based reconstruction of undersampled MRI allows for a substantial reduction of scan times, with a 10-times acceleration demonstrating excellent image quality while preserving the accuracy of derived imaging biomarkers for the assessment of oncological treatment response. Our developments are available as open source software and hold considerable promise for increasing the accessibility to MRI, pending further prospective validation. FUNDING: Deutsche Forschungsgemeinschaft (German Research Foundation) and an Else Kröner Clinician Scientist Endowed Professorship by the Else Kröner Fresenius Foundation.
Subject(s)
Deep Learning , Glioblastoma , Humans , Artificial Intelligence , Biomarkers , Cohort Studies , Glioblastoma/diagnostic imaging , Magnetic Resonance Imaging , Retrospective StudiesABSTRACT
Response Assessment in Neuro-Oncology (RANO) response criteria have been established and were updated in 2023 for MRI-based response evaluation of diffuse gliomas in clinical trials. In addition, PET-based imaging with amino acid tracers is increasingly considered for disease monitoring in both clinical practice and clinical trials. So far, a standardised framework defining timepoints for baseline and follow-up investigations and response evaluation criteria for PET imaging of diffuse gliomas has not been established. Therefore, in this Policy Review, we propose a set of criteria for response assessment based on amino acid PET imaging in clinical trials enrolling participants with diffuse gliomas as defined in the 2021 WHO classification of tumours of the central nervous system. These proposed PET RANO criteria provide a conceptual framework that facilitates the structured implementation of PET imaging into clinical research and, ultimately, clinical routine. To this end, the PET RANO 1.0 criteria are intended to encourage specific investigations of amino acid PET imaging of gliomas.
Subject(s)
Glioma , Neurology , Humans , Glioma/diagnostic imaging , Glioma/therapy , Amino Acids , Internal Medicine , Positron-Emission Tomography , Transcription FactorsABSTRACT
A diagnosis of brain metastasis (BM) significantly affects quality of life in patients with metastatic renal cell cancer (mRCC). Although systemic treatments have shown efficacy in mRCC, active surveillance (AS) is still commonly used in clinical practice. In this single-center cohort study, we assessed the impact of different initial treatment strategies for metastatic RCC (mRCC) on the development of BM. All consecutive patients diagnosed with mRCC between 2011 and 2022 were included at the Erasmus MC Cancer Institute, the Netherlands, and a subgroup of patients with BM was selected. In total, 381 patients with mRCC (ECM, BM, or both) were identified. Forty-six patients had BM of whom 39 had metachronous BM (diagnosed ≥1 month after ECM). Twenty-five (64.1%) of these 39 patients with metachronous BM had received prior systemic treatment for ECM and 14 (35.9%) patients were treatment naive at BM diagnosis. The median BM-free survival since ECM diagnosis was significantly longer (p = .02) in previously treated patients (29.0 [IQR 12.6-57.0] months) compared to treatment naive patients (6.8 [IQR 1.0-7.0] months). In conclusion, patients with mRCC who received systemic treatment for ECM prior to BM diagnosis had a longer BM-free survival as compared to treatment naïve patients. These results emphasize the need for careful evaluation of treatment strategies, and especially AS, for patients with mRCC.
Subject(s)
Brain Neoplasms , Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Carcinoma, Renal Cell/secondary , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/therapy , Brain Neoplasms/secondary , Brain Neoplasms/therapy , Male , Female , Kidney Neoplasms/pathology , Middle Aged , Aged , Quality of Life , Retrospective Studies , Netherlands/epidemiologyABSTRACT
PURPOSE: To provide practice guideline/procedure standards for diagnostics and therapy (theranostics) of meningiomas using radiolabeled somatostatin receptor (SSTR) ligands. METHODS: This joint practice guideline/procedure standard was collaboratively developed by the European Association of Nuclear Medicine (EANM), the Society of Nuclear Medicine and Molecular Imaging (SNMMI), the European Association of Neurooncology (EANO), and the PET task force of the Response Assessment in Neurooncology Working Group (PET/RANO). RESULTS: Positron emission tomography (PET) using somatostatin receptor (SSTR) ligands can detect meningioma tissue with high sensitivity and specificity and may provide clinically relevant information beyond that obtained from structural magnetic resonance imaging (MRI) or computed tomography (CT) imaging alone. SSTR-directed PET imaging can be particularly useful for differential diagnosis, delineation of meningioma extent, detection of osseous involvement, and the differentiation between posttherapeutic scar tissue and tumour recurrence. Moreover, SSTR-peptide receptor radionuclide therapy (PRRT) is an emerging investigational treatment approach for meningioma. CONCLUSION: These practice guidelines will define procedure standards for the application of PET imaging in patients with meningiomas and related SSTR-targeted PRRTs in routine practice and clinical trials and will help to harmonize data acquisition and interpretation across centers, facilitate comparability of studies, and to collect larger databases. The current document provides additional information to the evidence-based recommendations from the PET/RANO Working Group regarding the utilization of PET imaging in meningiomas Galldiks (Neuro Oncol. 2017;19(12):1576-87). The information provided should be considered in the context of local conditions and regulations.
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BACKGROUND: The health-related quality of life (HRQoL) and cognition are important indicators for the quality of survival in patients with high-grade glioma (HGG). However, data on long-term survivors and their caregivers are scarce. We aim to investigate the interaction between cognition and HRQoL in long-term survivors, their caregivers' evaluations, and the effect on caregiver strain and burden. METHODS: 21 long-term HGG (8 WHO grade III and 13 WHO grade IV) survivors (survival ≥ 5 years) and 15 caregivers were included. Cognition (verbal memory, attention, executive functioning, and language), HRQoL, anxiety and depression, caregiver strain, and caregiver burden were assessed with standardized measures. Questionnaires were completed by patients and/or their caregivers. RESULTS: Mean survival was 12 years (grade III) and 8 years (grade IV). Cognition was significantly impaired with a large individual variety. Patients' general HRQoL was not impaired but all functioning scales were deviant. Patient-proxy agreement was found in most HRQoL subscales. Three patients (14%) showed indications of anxiety or depression. One-third of the caregivers reported a high caregiver strain or a high burden. Test scores for attention, executive functioning, language, and/or verbal memory were correlated with perceived global health status, cognitive functioning, and/or communication deficits. Caregiver burden was not related to cognitive deficits. CONCLUSIONS: In long-term HGG survivors maintained HRQoL seems possible even when cognition is impaired in a large variety at the individual level. A tailored approach is therefore recommended to investigate the cognitive impairments and HRQoL in patients and the need for patient and caregiver support.
Subject(s)
Glioma , Quality of Life , Humans , Quality of Life/psychology , Caregivers/psychology , Glioma/psychology , Surveys and Questionnaires , Cognition , Survivors/psychologyABSTRACT
H3 K27M-mutant diffuse glioma is a recently identified brain tumor associated with poor prognosis. As of 2016, it is classified by the World Health Organization as a distinct form of grade IV glioma. Despite recognition as an important prognostic and diagnostic feature in diffuse glioma, radiation remains the sole standard of care and no effective systemic therapies are available for H3K27M mutant tumors. This review will detail treatment interventions applied to diffuse midline glioma and diffuse intrinsic pontine glioma (DIPG) prior to the identification of the H3 K27M mutation, the current standard-of-care for H3 K27M-mutant diffuse glioma treatment, and ongoing clinical trials listed on www.clinicaltrials.gov evaluating novel therapeutics in this population. Current clinical trials were identified using clinicaltrials.gov, and studies qualifying for this analysis were active or ongoing interventional trials that evaluated a therapy in at least 1 treatment arm or cohort comprised exclusively of patients with DIPG and H3 K27M-mutant glioma. Forty-one studies met these criteria, including trials evaluating H3 K27M vaccination, chimeric antigen receptor T-cell therapy, and small molecule inhibitors. Ongoing evaluation of novel therapeutics is necessary to identify safe and effective interventions in this underserved patient population.
Subject(s)
Diffuse Intrinsic Pontine Glioma , Glioma , Histones , Mutation , Humans , Brain Neoplasms/therapy , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Brain Stem Neoplasms/therapy , Brain Stem Neoplasms/genetics , Brain Stem Neoplasms/pathology , Diffuse Intrinsic Pontine Glioma/therapy , Diffuse Intrinsic Pontine Glioma/genetics , Diffuse Intrinsic Pontine Glioma/pathology , Glioma/genetics , Glioma/therapy , Glioma/pathology , Histones/genetics , PrognosisABSTRACT
Gliomas are the most common malignant primary brain tumours in adults and cannot usually be cured with standard cancer treatments. Gliomas show intratumoural and intertumoural heterogeneity at the histological and molecular levels, and they frequently contain mutations in the isocitrate dehydrogenase 1 (IDH1) or IDH2 gene. IDH-mutant adult-type diffuse gliomas are subdivided into grade 2, 3 or 4 IDH-mutant astrocytomas and grade 2 or 3 IDH-mutant, 1p19q-codeleted oligodendrogliomas. The product of the mutated IDH genes, D-2-hydroxyglutarate (D-2-HG), induces global DNA hypermethylation and interferes with immunity, leading to stimulation of tumour growth. Selective inhibitors of mutant IDH, such as ivosidenib and vorasidenib, have been shown to reduce D-2-HG levels and induce cellular differentiation in preclinical models and to induce MRI-detectable responses in early clinical trials. The phase III INDIGO trial has demonstrated superiority of vorasidenib, a brain-penetrant pan-mutant IDH inhibitor, over placebo in people with non-enhancing grade 2 IDH-mutant gliomas following surgery. In this Review, we describe the pathway of development of IDH inhibitors in IDH-mutant low-grade gliomas from preclinical models to clinical trials. We discuss the practice-changing implications of the INDIGO trial and consider new avenues of investigation in the field of IDH-mutant gliomas.
Subject(s)
Brain Neoplasms , Glioma , Isocitrate Dehydrogenase , Humans , Isocitrate Dehydrogenase/genetics , Isocitrate Dehydrogenase/antagonists & inhibitors , Glioma/drug therapy , Glioma/genetics , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Animals , Clinical Trials as Topic , Enzyme Inhibitors/therapeutic use , Enzyme Inhibitors/pharmacologyABSTRACT
Low-grade gliomas present a formidable challenge in neuro-oncology because of the challenges imposed by the blood-brain barrier, predilection for the young adult population, and propensity for recurrence. In the past two decades, the systematic examination of genomic alterations in adults and children with primary brain tumors has uncovered profound new insights into the pathogenesis of these tumors, resulting in more accurate tumor classification and prognostication. It also identified several common recurrent genomic alterations that now define specific brain tumor subtypes and have provided a new opportunity for molecularly targeted therapeutic intervention. Adult-type diffuse low-grade gliomas are frequently associated with mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), resulting in production of 2-hydroxyglutarate, an oncometabolite important for tumorigenesis. Recent studies of IDH inhibitors have yielded promising results in patients at early stages of disease with prolonged progression-free survival (PFS) and delayed time to radiation and chemotherapy. Pediatric-type gliomas have high rates of alterations in BRAF, including BRAF V600E point mutations or BRAF-KIAA1549 rearrangements. BRAF inhibitors, often combined with MEK inhibitors, have resulted in radiographic response and improved PFS in these patients. This article reviews emerging approaches to the treatment of low-grade gliomas, including a discussion of targeted therapies and how they integrate with the current treatment modalities of surgical resection, chemotherapy, and radiation.
Subject(s)
Brain Neoplasms , Glioma , Isocitrate Dehydrogenase , Neoplasm Grading , Humans , Glioma/genetics , Glioma/therapy , Glioma/drug therapy , Glioma/pathology , Isocitrate Dehydrogenase/genetics , Brain Neoplasms/genetics , Brain Neoplasms/therapy , Brain Neoplasms/drug therapy , Disease Management , Mutation , Molecular Targeted TherapyABSTRACT
Historically, patients with brain metastases (BMs) have been characterized by few systemic treatment options and poor prognosis. The recent introduction of next-generation anticancer therapies such as molecular targeted agents and immunotherapy have revolutionized the clinical decision-making process of this sub-population, posing new challenges to physicians. In this review, current evidence for the use of checkpoint inhibitors and targeted therapies in patients with BMs are discussed, with a focus on lung cancer, breast cancer, melanoma and renal cell carcinoma, providing suggestions and potential workflows for daily clinical practice. Several other on-going and future challenges, such as clinical trials design, ways to improve CNS penetration of novel drugs and unique molecular characteristics of BMs, are also discussed. The aim is producing an updated and easy-to-read guide for physicians, to improve decision-making in clinical practice.
Subject(s)
Antineoplastic Agents , Brain Neoplasms , Kidney Neoplasms , Lung Neoplasms , Melanoma , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Melanoma/therapy , Brain Neoplasms/drug therapy , Brain Neoplasms/secondary , Antineoplastic Agents/therapeutic use , Immunotherapy , Kidney Neoplasms/drug therapyABSTRACT
BACKGROUND: Zotiraciclib (TG02) is an oral multi-cyclin dependent kinase (CDK) inhibitor thought to inhibit tumor growth via CDK-9-dependent depletion of survival proteins such as c-MYC and MCL-1 which are frequently overexpressed in glioblastoma. METHODS: EORTC 1608 (NCT03224104) (STEAM) had a three parallel group (A,B,C) phase Ib, open-label, non-randomized, multicenter design in IDH wild-type newly diagnosed glioblastoma or anaplastic astrocytoma. Groups A and B explored the maximum tolerated dose (MTD) of TG02 in elderly patients, in combination with hypofractionated radiotherapy alone (group A) or temozolomide alone (group B), according to O6-methylguanine DNA methyltransferase promoter methylation status determined centrally. Group C explored single agent activity of TG02 at first relapse after temozolomide chemoradiotherapy with a primary endpoint of progression-free survival at 6 months (PFS-6). Tumor expression of CDK-9, c-MYC and MCL-1 was determined by immunohistochemistry. RESULTS: The MTD was 150 mg twice weekly in combination with radiotherapy alone (group A) or temozolomide alone (group B). Two dose-limiting toxicities were observed at 150 mg: one in group A (grade 3 seizure), one in group B (multiple grade 1 events). Main toxicities included neutropenia, gastrointestinal disorders and hepatotoxicity. PFS-6 in group C was 6.7%. CDK-9, c-MYC and MCL-1 were confirmed to be expressed and their expression was moderately cross-correlated. High protein levels of MCL-1 were associated with inferior survival. CONCLUSIONS: TG02 exhibits overlapping toxicity with alkylating agents and low single agent clinical activity in recurrent glioblastoma. The role of CDK-9 and its down-stream effectors as prognostic factors and therapeutic targets in glioblastoma warrants further study.
Subject(s)
Brain Neoplasms , Glioblastoma , Heterocyclic Compounds, 4 or More Rings , Humans , Aged , Glioblastoma/drug therapy , Glioblastoma/radiotherapy , Temozolomide/therapeutic use , Dacarbazine/therapeutic use , Myeloid Cell Leukemia Sequence 1 Protein/therapeutic use , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Brain Neoplasms/radiotherapy , Neoplasm Recurrence, Local/drug therapy , Enzyme Inhibitors , Antineoplastic Agents, Alkylating/therapeutic useABSTRACT
PURPOSE: IDH-mutant glioma are classified as oligodendroglioma or astrocytoma on the basis of 1p19q-codeletion. Whether prognostic factors are similar between these tumor types is not well understood. EXPERIMENTAL DESIGN: Retrospective cohort study. Molecular characterization was performed with targeted next-generation sequencing. Tumor volumes were calculated using semi-automatic 3D segmentation on all pre- and postoperative MRI-scans. Overall survival was assessed with Cox proportional hazards model. RESULTS: 383 patients with newly diagnosed IDH-mutant glioma were followed-up for a median of 7.2 years. Grade 3 and grade 4 patients had significantly lower Karnofsky performance, with tumors having more contrast-enhancement. Patients also received more aggressive post-surgery treatment. Postoperative tumor volume is significantly and independently associated with survival (HR per cm3 1.19, 95% CI 1.03 - 1.39) in IDH-mutant glioma. Separate analysis of oligodendroglioma and astrocytoma showed a significant association of postoperative tumor volume in astrocytoma, but not in oligodendroglioma. Higher age and histological tumor grade were associated with worse survival in patients with oligodendroglioma, but not with astrocytoma. CONCLUSIONS: Our data support an initial strategy of extensive resection in both oligodendroglioma and astrocytoma patients. Other important prognostic factors differ between these tumor types, urging researchers and clinicians to keep treating these tumors as separate entities.
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L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare neurometabolic disorder characterized by accumulation of L2-hydroxyglutarate (L-2-HG) due to mutations in the L2HGDH gene. L-2-HGA patients have a significantly increased lifetime risk of central nervous system (CNS) tumors. Here, we present a 16-year-old girl with L-2-HGA who developed a tumor in the right cerebral hemisphere, which was discovered after left-sided neurological deficits of the patient. Histologically, the tumor had a high-grade diffuse glioma phenotype. DNA sequencing revealed the inactivating homozygous germline L2HGDH mutation as well as inactivating mutations in TP53, BCOR and NF1. Genome-wide DNA-methylation analysis was unable to classify the tumor with high confidence. More detailed analysis revealed that this tumor clustered amongst IDH-wildtype gliomas by methylation profiling and did not show the glioma CpG island methylator phenotype (G-CIMP) in contrast to IDH-mutant diffuse gliomas with accumulated levels of D-2-HG, the stereoisomer of L-2-HD. These findings were against all our expectations given the inhibitory potential of 2-HG on DNA-demethylation enzymes. Our final integrated histomolecular diagnosis of the tumor was diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype. Due to rapid tumor progression the patient died nine months after initial diagnosis. In this manuscript, we provide extensive molecular characterization of the tumor as well as a literature review focusing on oncogenetic considerations of L-2-HGA-associated CNS tumors.
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BACKGROUND: H3 K27M-mutant diffuse glioma primarily affects children and young adults, is associated with a poor prognosis, and no effective systemic therapy is currently available. ONC201 (dordaviprone) has previously demonstrated efficacy in patients with recurrent disease. This phase 3 trial evaluates ONC201 in patients with newly diagnosed H3 K27M-mutant glioma. METHODS: ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international phase 3 study of ONC201 in newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy are randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on 2 consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS); PFS is assessed by response assessment in neuro-oncology high-grade glioma criteria (RANO-HGG) by blind independent central review. Secondary objectives include safety, additional efficacy endpoints, clinical benefit, and quality of life. Eligible patients have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility is not restricted by age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in multiple international sites.
Subject(s)
Brain Neoplasms , Glioma , Mutation , Humans , Glioma/genetics , Glioma/drug therapy , Glioma/pathology , Double-Blind Method , Brain Neoplasms/genetics , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Adult , Male , Female , Histones/genetics , Adolescent , Child , Young Adult , Prognosis , Survival Rate , Quality of Life , Middle Aged , Follow-Up Studies , AgedABSTRACT
BACKGROUND AND OBJECTIVES: Hydrocephalus is a common radiologic sign in patients with leptomeningeal metastasis (LM) from solid tumors which can be assessed using the Evans index (EI). Here, we explored the prognostic value of ventricular size in LM. METHODS: We identified patients with LM from solid tumors by chart review at 3 academic hospitals to explore the prognostic associations of the EI at diagnosis, first follow-up, and progression. RESULTS: We included 113 patients. The median age was 58.3 years (interquartile range [IQR] 46.1-65.8), 41 patients (36%) were male, and 72 patients (64%) were female. The most frequent cancers were lung cancer (n = 39), breast cancer (n = 36), and melanoma (n = 23). The median EI at baseline was 0.28 (IQR 0.26-0.31); the EI value was 0.27 or more in 67 patients (59%) and 0.30 or more in 37 patients (33%). Among patients with MRI follow-up, the EI increased by 0.01 or more in 16 of 31 patients (52%), including 8 of 30 patients (30%) without and 10 of 17 patients (59%) with LM progression at first follow-up. At LM progression, an increase of EI of 0.01 or more was noted in 18 of 34 patients (53%). The median survival was 2.9 months (IQR 1-7.2). Patients with a baseline EI below 0.27 had a longer survival than those with an EI of 0.27 or more (5.3 months, IQR 2.4-10.8, vs 1.3 months, IQR 0.6-4.1) (HR 1.70, 95% CI 1.135-2.534, p = 0.0099). The median survival was 3.7 months (IQR 1.4-8.3) with an EI below 0.30 vs 1.8 months (IQR 0.8-4.1) with an EI of 0.30 or more (HR 1.40, 95% CI 0.935-1.243, p = 0.1113). Among patients with follow-up scans available, the overall survival was 9.4 months (IQR 5.6-21.0) for patients with stable or decreased EI at first follow-up as opposed to 5.6 months (IQR 2.5-10.5) for those with an increase in the EI (HR 1.08, 95% CI 0.937-1.243; p = 0.300). DISCUSSION: The EI at baseline is prognostic in LM. An increase of EI during follow-up may be associated with inferior LM progression-free survival. Independent validation cohorts with larger sample size and evaluation of confounding factors will help to better define the clinical utility of EI assessments in LM.
Subject(s)
Breast Neoplasms , Lung Neoplasms , Meningeal Carcinomatosis , Humans , Male , Female , Middle Aged , Prognosis , Retrospective Studies , Lung Neoplasms/pathology , Meningeal Carcinomatosis/diagnostic imaging , Meningeal Carcinomatosis/secondary , Breast Neoplasms/pathologyABSTRACT
Accurate grading of IDH-mutant gliomas defines patient prognosis and guides the treatment path. Histological grading is however difficult and, apart from CDKN2A/B homozygous deletions in IDH-mutant astrocytomas, there are no other objective molecular markers used for grading. Experimental Design: RNA-sequencing was conducted on primary IDH-mutant astrocytomas (n=138) included in the prospective CATNON trial, which was performed to assess the prognostic effect of adjuvant and concurrent temozolomide. We integrated the RNA sequencing data with matched DNA-methylation and NGS data. We also used multi-omics data from IDH-mutant astrocytomas included in the TCGA dataset and validated results on matched primary and recurrent samples from the GLASS-NL study. We used the DNA-methylation profiles to generate a Continuous Grading Coefficient (CGC) that is based on classification scores derived from a CNS-tumor classifier. We found that the CGC was an independent predictor of survival outperforming current WHO-CNS5 and methylation-based classification. Our RNA-sequencing analysis revealed four distinct transcription clusters that were associated with i) an upregulation of cell cycling genes; ii) a downregulation of glial differentiation genes; iii) an upregulation of embryonic development genes (e.g. HOX, PAX and TBX) and iv) an upregulation of extracellular matrix genes. The upregulation of embryonic development genes was associated with a specific increase of CpG island methylation near these genes.
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BACKGROUND: The aim of this study was to provide quantitative evidence for the potential of PSMA-targeting radioligand therapy (RLT) as treatment approach for malignant brain tumours, and to explore whether tumour uptake could be enhanced by super-selective intra-arterial (ssIA)-administration. METHODS: Ten patients (n = 5 high-grade glioma, n = 5 brain metastasis) received 1.5 MBq/kg [68Ga]Ga-PSMA-11 intravenously and, within 7 days, intra-arterially (i.e., selectively in tumour-feeding arteries), followed twice by PET-MRI at 90, 165 and 240 min post-injection. Patient safety was monitored for each procedure. Standardised uptake values (SUVs) were obtained for tumour, healthy-brain, salivary glands and liver. Tumour-to-salivary-gland (T/SG) and tumour-to-liver (T/L) uptake-ratios were calculated. FINDINGS: No adverse events requiring study termination occurred. All patients showed uptake of [68Ga]Ga-PSMA-11 at the tumour site. Uptake was a median 15-fold higher following ssIA-administration (SUVmax median: 142.8, IQR: 102.8-245.9) compared to IV-administration (10.5, IQR:7.5-13.0). According to the bootstrap analysis, mean SUVmax after ssIA (168.8, 95% CI: 110.6-227.0) was well beyond the 95% confidence-interval of IV administration (10.5, 95% CI: 8.4-12.7). Uptake in healthy-brain was negligible, independent of administration route (SUVmean <0.1-0.1). Off-target uptake was comparable, resulting in more favourable T/SG- and T/L-ratios of 8.4 (IQR: 4.4-11.5) and 26.5 (IQR: 14.0-46.4) following ssIA, versus 0.5 (IQR: 0.4-0.7) and 1.8 (IQR: 1.0-2.7) for IV-administration. INTERPRETATION: ssIA-administration is safe and leads to a median fifteen-fold higher radioligand uptake at the tumour site, therewith qualifying more patients for treatment and enhancing the potential of therapy. These results open new avenues for the development of effective RLT-based treatment strategies for patients with brain tumours. FUNDING: Semmy Foundation.
Subject(s)
Brain Neoplasms , Gallium Isotopes , Gallium Radioisotopes , Humans , Brain , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/radiotherapy , Prospective StudiesABSTRACT
INTRODUCTION: A greater extent of resection of the contrast-enhancing (CE) tumour part has been associated with improved outcomes in glioblastoma. Recent results suggest that resection of the non-contrast-enhancing (NCE) part might yield even better survival outcomes (supramaximal resection, SMR). Therefore, this study evaluates the efficacy and safety of SMR with and without mapping techniques in high-grade glioma (HGG) patients in terms of survival, functional, neurological, cognitive and quality of life outcomes. Furthermore, it evaluates which patients benefit the most from SMR, and how they could be identified preoperatively. METHODS AND ANALYSIS: This study is an international, multicentre, prospective, two-arm cohort study of observational nature. Consecutive glioblastoma patients will be operated with SMR or maximal resection at a 1:1 ratio. Primary endpoints are (1) overall survival and (2) proportion of patients with National Institute of Health Stroke Scale deterioration at 6 weeks, 3 months and 6 months postoperatively. Secondary endpoints are (1) residual CE and NCE tumour volume on postoperative T1-contrast and FLAIR (Fluid-attenuated inversion recovery) MRI scans; (2) progression-free survival; (3) receipt of adjuvant therapy with chemotherapy and radiotherapy; and (4) quality of life at 6 weeks, 3 months and 6 months postoperatively. The total duration of the study is 5 years. Patient inclusion is 4 years, follow-up is 1 year. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee (METC Zuid-West Holland/Erasmus Medical Center; MEC-2020-0812). The results will be published in peer-reviewed academic journals and disseminated to patient organisations and media.
Subject(s)
Brain Neoplasms , Glioblastoma , Quality of Life , Humans , Brain Neoplasms/surgery , Glioblastoma/surgery , Magnetic Resonance Imaging , Multicenter Studies as Topic , Neurosurgical Procedures/methods , Prospective StudiesABSTRACT
BACKGROUND: The utility of liquid biopsies is well documented in several extracranial and intracranial (brain/leptomeningeal metastases, gliomas) tumors. METHODS: The RANO (Response Assessment in Neuro-Oncology) group has set up a multidisciplinary Task Force to critically review the role of blood and cerebrospinal fluid (CSF)-liquid biopsy in CNS lymphomas, with a main focus on primary central nervous system lymphomas (PCNSL). RESULTS: Several clinical applications are suggested: diagnosis of PCNSL in critical settings (elderly or frail patients, deep locations, and steroid responsiveness), definition of minimal residual disease, early indication of tumor response or relapse following treatments, and prediction of outcome. CONCLUSIONS: Thus far, no clinically validated circulating biomarkers for managing both primary and secondary CNS lymphomas exist. There is need of standardization of biofluid collection, choice of analytes, and type of technique to perform the molecular analysis. The various assays should be evaluated through well-organized central testing within clinical trials.
Subject(s)
Biomarkers, Tumor , Central Nervous System Neoplasms , Lymphoma , Humans , Liquid Biopsy/methods , Central Nervous System Neoplasms/diagnosis , Central Nervous System Neoplasms/cerebrospinal fluid , Lymphoma/diagnosis , Lymphoma/pathology , Lymphoma/blood , Biomarkers, Tumor/blood , PrognosisABSTRACT
The 2016 and 2021 World Health Organization (WHO) 2021 Classification of Central Nervous System (CNS) tumors have resulted in a major improvement of the classification of IDH-mutant gliomas. With more effective treatments many patients experience prolonged survival . However, treatment guidelines are often still based on information from historical series comprising both patients with IDHwt and IDH mutant tumors. They provide recommendations for radiotherapy and chemotherapy for so-called high-risk patients, usually based on residual tumor after surgery and age over 40. More up-to-date studies give a better insight into clinical, radiological and molecular factors associated with outcome of patients with IDH-mutant glioma. These insights should be used today for risk stratification and for treatment decisions. In many patients with an IDH-mutant grade 2 and grade 3 glioma, if carefully monitored postponing radiotherapy and chemotherapy is safe, and will not jeopardize overall outcome of patients. With the INDIGO trial showing patient benefit from the IDH inhibitor vorasidenib, there is a sizable population in which it seems reasonable to try this class of agents before recommending radio-chemotherapy with its delayed adverse event profile affecting quality of survival. Ongoing trials should help to further identify the patients that are benefiting from this treatment.